Drug delivery systems and methods for treatment of bladder cancer with gemcitabine

Abstract

Drug delivery devices and methods are provided for administering gemcitabine to a patient in need of treatment of bladder cancer by intravesically administering gemcitabine into the bladder of the patient to achieve a sustained concentration of the gemcitabine in urine in the bladder sufficient to produce a therapeutically effective concentration of the gemcitabine in the tissues of the bladder. In embodiments, the local administration into the patient's bladder is at a mean average amount of from 1 mg/day to about 300 mg/day of the gemcitabine (FBE).

We claim: 
     
         1 . A method of treatment of bladder cancer in a patient, comprising:
 locally administering gemcitabine into the urinary bladder of the patient to achieve a sustained concentration of the gemcitabine in urine in the bladder sufficient to produce a therapeutic concentration of the gemcitabine in the bladder tissues,   wherein the locally administering into the patient's bladder is at a mean average amount of from 1 mg/day to about 300 mg/day of the gemcitabine (FBE).   
     
     
         2 . The method of  claim 1 , wherein the locally administering into the patient's bladder is at a mean average amount of from 1 mg/day to 200 mg/day of the gemcitabine (FBE). 
     
     
         3 . The method of  claim 1 , wherein the locally administering into the patient's bladder is at a mean average amount of from 5 mg/day to 100 mg/day of the gemcitabine (FBE). 
     
     
         4 . The method of  claim 1 , wherein the locally administering into the patient's bladder is at a mean average amount of from 10 mg/day to 50 mg/day of the gemcitabine (FBE). 
     
     
         5 . The method of  claim 1 , wherein the locally administering into the patient's bladder is at a mean average amount of from 15 mg/day to 25 mg/day of the gemcitabine (FBE). 
     
     
         6 . The method of  claim 1 , wherein the locally administering into the patient's bladder is at a mean average amount of about 20 mg/day of the gemcitabine (FBE). 
     
     
         7 . The method of  claim 1 , wherein the locally administering into the patient's bladder is continuous over a period from 1 day to 30 days. 
     
     
         8 . The method of  claim 1 , wherein the locally administering into the patient's bladder is intermittent over a period from 1 day to 30 days. 
     
     
         9 . The method of  claim 1 , wherein the locally administering into the patient's bladder is intermittent or continuous over a period from 3 days to 21 days. 
     
     
         10 . The method of  claim 1 , wherein the locally administering into the patient's bladder is continuous over a period from 7 day to 21 days. 
     
     
         11 . The method of  claim 1 , wherein the gemcitabine is delivered into the bladder from an intravesical drug delivery device which continuously releases the gemcitabine into the urine in the bladder over a sustained period. 
     
     
         12 . The method of  claim 11 , wherein the sustained period is 1 day to 21 days. 
     
     
         13 . The method of  claim 11 , wherein the intravesical drug delivery device comprises a housing which contains and controllably releases the gemcitabine and is elastically deformable between a retention shape configured to retain the device in a patient's bladder and a deployment shape for passage of the device through the patient's urethra. 
     
     
         14 . The method of  claim 13 , wherein the gemcitabine contained in the housing is in a non-liquid form. 
     
     
         15 . The method of  claim 14 , wherein the non-liquid form is selected from the group consisting of tablets, granules, semisolids, capsules, and combinations thereof. 
     
     
         16 . The method of  claim 1 , wherein the gemcitabine is delivered into the bladder from a coating substance applied to the bladder, which coating substance releases the gemcitabine into the urine in the bladder over a sustained period. 
     
     
         17 . The method of  claim 16 , wherein the coating substance comprises a mucoadhesive formulation. 
     
     
         18 . The method of  claim 17 , wherein the sustained period is from 1 day to 14 days. 
     
     
         19 . The method of  claim 17 , wherein the sustained period is from 1 day to 7 days. 
     
     
         20 . The method of  claim 1 , wherein the locally administering comprises pumping a liquid form of the gemcitabine into the bladder through a urethral or suprapubic catheter which is deployed into the bladder. 
     
     
         21 . The method of  claim 20 , wherein the locally administering into the patient's bladder is continuous or intermittent over a period from 1 day to 7 days. 
     
     
         22 . The method of  claim 1 , further comprising administering at least a second therapeutic agent to the patient. 
     
     
         23 . The method of  claim 22 , wherein the second therapeutic agent is administered intravesically. 
     
     
         24 . The method of  claim 1 , further comprising administering urea or another solubility altering agent into the bladder in an amount effective to enhance or otherwise alter solubilization of the gemcitabine. 
     
     
         25 . The method of  claim 24 , wherein the urea or other solubility altering agent is released from an intravesical device releasing the gemcitabine. 
     
     
         26 . A drug delivery device comprising:
 a housing configured for intravesical insertion; and   a dosage form comprising gemcitabine,   wherein the housing holds the dosage form and is configured to release the gemcitabine into the bladder in an amount therapeutically effective for the treatment of the bladder,   wherein the device is configured to release gemcitabine into the bladder at a mean average amount of from 1 mg/day to about 300 mg/day of the gemcitabine.   
     
     
         27 . The device of  claim 26 , wherein the housing releases the gemcitabine by diffusion through a drug permeable polymeric wall. 
     
     
         28 . The device of  claim 26 , wherein the housing releases the gemcitabine without a predefined release aperture. 
     
     
         29 . The device of  claim 26 , wherein the housing comprises a release orifice in communication with a drug reservoir in which the gemcitabine is contained along with (i) a viscosity enhancing agent, (ii) an osmotic agent, or (iii) a combination of a viscosity enhancing agent and an osmotic agent. 
     
     
         30 . The device of  claim 29 , wherein the gemcitabine is provided in a first region comprising one or more tablets and the osmotic agent and/or viscosity enhancing agent is/are provided in a second region comprising one or more tablets, wherein the first and second regions are discrete spaces within the drug reservoir.